PRSS57

Summary

PRSS57 (serine protease 57, HGNC:31397) is a protein-coding gene on chromosome 19p13.3, encoding Serine protease 57 (Q6UWY2). Serine protease that cleaves preferentially after Arg residues.

This gene encodes an arginine-specific serine protease and member of the peptidase S1 family of proteins. The encoded protein may undergo proteolytic activation before storage in azurophil granules, in neutrophil cells of the immune system. Following neutrophil activation, the protease is released into the pericellular environment, where it may play a role in defense against microbial pathogens.

Source: NCBI Gene 400668 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 82 total
• MANE Select transcript: NM_001308209

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31397
Approved symbol	PRSS57
Name	serine protease 57
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ782
Ensembl gene	ENSG00000185198
Ensembl biotype	protein_coding
OMIM	621351
Entrez	400668

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000329267, ENST00000613411

RefSeq mRNA: 2 — MANE Select: NM_001308209 NM_001308209, NM_214710

CCDS: CCDS12041, CCDS77203

Canonical transcript exons

ENST00000329267 — 5 exons

Exon	Start	End
ENSE00001295633	685546	685922
ENSE00001308790	686925	687188
ENSE00001326807	691858	692002
ENSE00001387520	695352	695452
ENSE00003727412	694814	694967

Expression profiles

Bgee: expression breadth broad, 46 present calls, max score 88.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 13.8915 / max 2773.1914, expressed in 86 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177919	10.1094	72
177920	1.5382	50
177921	1.5044	43
177923	0.5180	34
177922	0.1521	22
177924	0.0694	14

Top tissues by expression

91 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bone marrow	UBERON:0002371	88.84	gold quality
bone marrow cell	CL:0002092	81.39	gold quality
granulocyte	CL:0000094	78.71	gold quality
monocyte	CL:0000576	73.00	gold quality
leukocyte	CL:0000738	72.95	gold quality
blood	UBERON:0000178	69.40	gold quality
spleen	UBERON:0002106	56.43	gold quality
right lobe of liver	UBERON:0001114	43.72	gold quality
hindlimb stylopod muscle	UBERON:0004252	43.22	silver quality
upper lobe of left lung	UBERON:0008952	42.38	gold quality
lung	UBERON:0002048	40.87	gold quality
sural nerve	UBERON:0015488	40.66	gold quality
placenta	UBERON:0001987	40.47	gold quality
mucosa of stomach	UBERON:0001199	39.95	silver quality
liver	UBERON:0002107	39.56	gold quality
lymph node	UBERON:0000029	39.44	gold quality
right uterine tube	UBERON:0001302	39.10	silver quality
left ovary	UBERON:0002119	39.05	gold quality
ovary	UBERON:0000992	38.79	gold quality
right ovary	UBERON:0002118	38.62	silver quality
apex of heart	UBERON:0002098	37.56	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
skeletal muscle tissue	UBERON:0001134	36.54	gold quality
subcutaneous adipose tissue	UBERON:0002190	36.52	silver quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
adipose tissue	UBERON:0001013	36.44	silver quality
omental fat pad	UBERON:0010414	36.36	silver quality
left adrenal gland cortex	UBERON:0035825	36.07	silver quality
left adrenal gland	UBERON:0001234	35.53	silver quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	1341.27
E-MTAB-10432	yes	1162.31
E-CURD-112	yes	948.92
E-HCAD-6	yes	846.86
E-MTAB-7407	yes	826.19
E-CURD-79	yes	795.38
E-MTAB-9067	yes	702.62
E-CURD-77	yes	603.63
E-HCAD-4	yes	569.98
E-ANND-5	yes	409.79
E-GEOD-89232	yes	264.91
E-HCAD-1	yes	16.98
E-CURD-122	yes	15.59
E-MTAB-6701	yes	15.57
E-ANND-3	yes	14.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting PRSS57, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4491	96.53	66.20	935

Literature-anchored findings (GeneRIF, showing 3)

• cathepsin C was identified as the activator of NSP4 in vivo, as cathepsin C deficiency resulted in a complete absence of NSP4 in a Papillon-Lefevre patient (PMID:23904161)
• Structural insights in to substrate recognition by the trypsin-fold protease NSP4. (PMID:25156428)
• The NSP4 T492I mutation increases SARS-CoV-2 infectivity by altering non-structural protein cleavage. (PMID:37402373)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Prss57	ENSMUSG00000020323
rattus_norvegicus	Prss57	ENSRNOG00000025293

Paralogs (14): PRSS33 (ENSG00000103355), PLAT (ENSG00000104368), PLG (ENSG00000122194), PLGLB2 (ENSG00000125551), PRSS37 (ENSG00000165076), PRSS27 (ENSG00000172382), KLK15 (ENSG00000174562), PLGLB1 (ENSG00000183281), TMPRSS12 (ENSG00000186452), OVCH1 (ENSG00000187950), PRSS48 (ENSG00000189099), GZMM (ENSG00000197540), KLK9 (ENSG00000213022), PRSS50 (ENSG00000283706)

Protein

Protein identifiers

Serine protease 57 — Q6UWY2 (reviewed: Q6UWY2)

Alternative names: Neutrophil serine protease 4, Serine protease 1-like protein 1

All UniProt accessions (2): A0A0A0MR61, Q6UWY2

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease that cleaves preferentially after Arg residues. Can also cleave after citrulline (deimidated arginine) and methylarginine residues.

Subcellular location. Cytoplasmic granule lumen. Secreted.

Tissue specificity. Detected in peripheral blood neutrophil granulocytes, but not in other types of leukocytes. Detected in neutrophils and neutrophil precursors in bone marrow (at protein level). Detected in myeloblasts and promyelocytes in bone marrow.

Post-translational modifications. After cleavage of the signal peptide, the N-terminus is probably further processed by CTSC. Processing by CTSC is probably required for accumulation in cytoplasmic granules; in the absence of CTSC the protein does not accumulate. N-glycosylated.

Activity regulation. Inhibited by SERPINA1, SERPINC1 and SERPING1.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (2): NP_001295138, NP_999875 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR043504

Pfam: PF00089

UniProt features (38 total): strand 15, helix 5, disulfide bond 4, mutagenesis site 3, active site 3, turn 2, glycosylation site 2, signal peptide 1, chain 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4Q7Z	X-RAY DIFFRACTION	1.4
4Q7X	X-RAY DIFFRACTION	2.55
4Q7Y	X-RAY DIFFRACTION	2.7
4Q80	X-RAY DIFFRACTION	3.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWY2-F1	89.75	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 74 (charge relay system); 122 (charge relay system); 218 (charge relay system)

Disulfide bonds (4): 188–202, 214–239, 59–75, 157–224

Glycosylation sites (2): 129, 189

Mutagenesis-validated functional residues (3):

Position	Phenotype
213	decreases enzyme activity tenfold.
215	decreases enzyme activity tenfold. decreases enzyme activity twentyfold; when associated with g-236.
235	decreases enzyme activity tenfold. decreases enzyme activity twentyfold; when associated with a-215.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 32 (showing top): GOCC_SECRETORY_GRANULE, GOBP_PROTEIN_MATURATION, GOMF_GLYCOSAMINOGLYCAN_BINDING, GOMF_HEPARIN_BINDING, GOCC_SECRETORY_VESICLE, GOCC_VESICLE_LUMEN, GOCC_VACUOLAR_LUMEN, GOBP_PROTEOLYSIS, chr19p13, GOMF_SULFUR_COMPOUND_BINDING, GOMF_PEPTIDASE_ACTIVITY, CHYLA_CBFA2T3_TARGETS_UP, GOCC_AZUROPHIL_GRANULE_LUMEN, GOCC_AZUROPHIL_GRANULE, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY

GO Biological Process (2): proteolysis (GO:0006508), protein maturation (GO:0051604)

GO Molecular Function (5): serine-type endopeptidase activity (GO:0004252), heparin binding (GO:0008201), serine-type peptidase activity (GO:0008236), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), azurophil granule lumen (GO:0035578), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
gene expression	1
endopeptidase activity	1
serine-type peptidase activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
peptidase activity	1
serine hydrolase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRSS57	SH2D3C	Q8N5H7	998
PRSS57	SH2D3A	Q9BRG2	997
PRSS57	SPECC1	Q5M775	874
PRSS57	MRPL58	Q14197	695
PRSS57	MPO	P05164	675
PRSS57	PPP1CA	P08129	643
PRSS57	TLR2	O60603	619
PRSS57	KIR2DL4	P78400	609
PRSS57	HSPA5	P11021	582
PRSS57	CDK1	P06493	550
PRSS57	ACE2	Q9BYF1	545
PRSS57	ASZ1	Q8WWH4	541
PRSS57	IKBKG	Q9Y6K9	525
PRSS57	BECN1	Q14457	520
PRSS57	FURIN	P09958	514

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A1L453, A6NIE9, O43240, P07288, P15944, P20151, P20231, P33619, P49862, P51124, P51779, P83748, Q03238, Q14B24, Q15661, Q16651, Q2L4Q9, Q2UVH8, Q571E5, Q5K2P8, Q5K2P9, Q61096, Q6BEA2, Q6DT45, Q6IE59, Q6IE62, Q6UWY2, Q76B45, Q7JIG6, Q7RTY9, Q7Z5A4, Q80WM7, Q8K4I7, Q920S2, Q92876, Q9BQR3, Q9BZJ3, Q9ER04, Q9ES87, Q9ESD1

Diamond homologs: A7WPL7, O35164, O35205, O46683, O60259, O88780, P00746, P00752, P00760, P00761, P00762, P00763, P00764, P00770, P00772, P00773, P04187, P06870, P06871, P07146, P07288, P08311, P08426, P08882, P08883, P08884, P09582, P09650, P10144, P11032, P11033, P11034, P12323, P12544, P12788, P13366, P15119, P16049, P17977, P18291

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

82 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

878 predictions. Top by Δscore:

Variant	Effect	Δscore
19:685918:TCGGC:T	acceptor_gain	0.9900
19:685919:CGGC:C	acceptor_gain	0.9900
19:685919:CGGCC:C	acceptor_gain	0.9900
19:685921:GC:G	acceptor_gain	0.9900
19:685921:GCCTG:G	acceptor_loss	0.9900
19:685922:CC:C	acceptor_gain	0.9900
19:685923:C:CC	acceptor_gain	0.9900
19:685923:CTGGA:C	acceptor_loss	0.9900
19:685924:T:A	acceptor_loss	0.9900
19:685928:G:GC	acceptor_gain	0.9900
19:686918:ATCTT:A	donor_loss	0.9900
19:686919:TCTTA:T	donor_loss	0.9900
19:686920:CTTA:C	donor_loss	0.9900
19:686921:TTACC:T	donor_loss	0.9900
19:686922:TA:T	donor_loss	0.9900
19:686923:A:AC	donor_gain	0.9900
19:686923:ACC:A	donor_loss	0.9900
19:686924:C:CC	donor_gain	0.9900
19:686924:CCGAG:C	donor_gain	0.9900
19:686993:T:TA	donor_gain	0.9900
19:687185:TCAG:T	acceptor_gain	0.9900
19:687186:CAG:C	acceptor_gain	0.9900
19:687186:CAGC:C	acceptor_gain	0.9900
19:687187:AG:A	acceptor_gain	0.9900
19:687188:GCTG:G	acceptor_loss	0.9900
19:687189:C:CC	acceptor_gain	0.9900
19:687190:T:A	acceptor_loss	0.9900
19:691852:GCT:G	donor_loss	0.9900
19:691853:CTCAC:C	donor_loss	0.9900
19:691854:TCACC:T	donor_loss	0.9900

AlphaMissense

1796 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:687084:C:A	W162C	0.996
19:687084:C:G	W162C	0.996
19:691874:T:A	D122V	0.996
19:691874:T:G	D122A	0.994
19:685866:G:C	F234L	0.990
19:685866:G:T	F234L	0.990
19:685868:A:G	F234L	0.990
19:691873:G:C	D122E	0.990
19:691873:G:T	D122E	0.990
19:691875:C:G	D122H	0.989
19:685797:C:A	W257C	0.988
19:685797:C:G	W257C	0.988
19:686965:C:G	C202S	0.988
19:686966:A:T	C202S	0.988
19:687007:C:G	C188S	0.987
19:687008:A:T	C188S	0.987
19:686994:C:A	W192C	0.985
19:686994:C:G	W192C	0.985
19:691874:T:C	D122G	0.985
19:691875:C:A	D122Y	0.985
19:686931:G:C	F213L	0.983
19:686931:G:T	F213L	0.983
19:686933:A:G	F213L	0.983
19:685806:A:C	F254L	0.982
19:685806:A:T	F254L	0.982
19:685808:A:G	F254L	0.982
19:685852:C:G	C239S	0.981
19:685853:A:T	C239S	0.981
19:685912:C:A	G219V	0.981
19:686929:C:G	C214S	0.981

dbSNP variants (sampled 300 via entrez): RS1000165420 (19:696384 C>T), RS1000485693 (19:686765 C>T), RS1000635845 (19:691790 G>A), RS1000771604 (19:691560 T>C), RS1000888372 (19:692577 C>T), RS1001180981 (19:694019 C>A), RS1001529340 (19:693056 T>C,G), RS1001587938 (19:696884 G>A,T), RS1001921555 (19:695817 C>A,T), RS1001984488 (19:687338 G>A,T), RS1002077843 (19:687113 C>T), RS1002103756 (19:692141 G>A,C), RS1002168418 (19:693198 C>A,T), RS1002392592 (19:695724 C>G), RS1003397392 (19:695521 G>A,T)

Disease associations

OMIM: gene MIM:621351 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): long QT syndrome (MONDO:0002442)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1875	Blood protein levels	7.000000e-107

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Cadmium Chloride	decreases expression, increases abundance	2
GSK-J4	decreases expression	1
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	decreases methylation	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Aldehydes	increases expression	1
Cadmium	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1

Clinical trials (associated diseases)

66 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea